Asian Journal of Medical Sciences 3(1): 17-22, 2011
ISSN: 2040-8773
© Maxwell Scientific Organization, 2011
Received: September 17, 2010
Accepted: October 27, 2010
Published: February 25, 2011
Clinical and Cytogenetic Effects in Habitants under Large Duration
Exposure of Endosulfan
1
R. Saraswathy, 1G. Alex, 1B.M. Basil, 1A.R.S. Badarinath, 1R. Girish, 1G. Ribu, 1V.G. Abilash,
2
G.D.J. Cruz and 3K.M. Marimuthu
1
Division of Biomolecules and Genetics, School of Bio Sciences and Technology,
VIT University, Vellore-632014, TamilNadu, India
²District Medical Officer, Kasaragod, Kerala, India
³Emeritus Professor, Madras University, Chennai, India
Abstract: No data is available on the genotoxic effects of long term exposure of endosulfan on human
population. A study was undertaken to examine the environmental long term endosulfan exposure ranging from
6 years to 40 years on the clinical and cytogenetic nature of human. The study population was composed of
eight families consisting of 35 individuals. They are permanent residents of the village situated below the
cashew plantation where endosulfan had been sprayed aerially. Thus the residents had the exposure of
endosulfan through aerial spray and subsequently through other contaminated environmental media for several
years. Clinical nature of all the 35 subjects were recorded with the help of the physicians and 11 of them
(31.4%) showed severe clinical deformity ranging from mental retardation to bone marrow cancer showing
neurotoxicity and immunotoxic effects of endosulfan exposure. The cytogenetic studies were carried out using
peripheral blood leucocyte cultures and giemsa banding technology and scoring chromosome aberrations as
endpoint. It was observed that chromosome aberration per cell was 0.121±0.09 which was significantly higher,
when compared with the control samples showing 0.04±0.0001. This study is the first of its kind in literature.
This study shows a clear relationship between the human health hazards and environmental pollutant.
Key words: Chromosome aberrations, endosulfan genotoxicity, environmental pollutant, neurotoxicity
insects in a wide variety of food and non-food crops. It
may also be used as a wood preservative.
Neurotoxicity and endocrine-disrupting potential of
endosulfan were demonstrated in animal experiments
(Hiremath and Kaliwal, 2002), in vitro assays
(Kang et al., 2001; Bisson and Hontela, 2002) and yeastbased reporter gene assays (Graumann et al., 1999).
Neurotoxicity is the major end point of concern in acute
endosulfan exposure in human beings and experimental
animals. No data are available for subacute or chronic
exposure to endosulfan in human subjects; however, the
subacute and chronic toxicity studies of endosulfan in
animals suggest that the liver, kidneys, immune system,
and testes are the main target organs [Agency for Toxic
Substances and Disease Registry (ATSDR), 2000].
Hence this study is undertaken in human subjects to
fulfill the lacunae. To our knowledge the results presented
here appear to be the first to demonstrate the genotoxic
effect of long duration exposure of endosulfan on human
population using cytogenetic and clinical parameters.
Endosulfan was the only pesticide that had been
aerially sprayed two to three times a year for more than 20
INTRODUCTION
Since the early 1940’s there has been a tremendous
proliferation of man made chemicals into the
environment. Of increasing concern is the fact that a
majority of these chemicals has not been evaluated for
potential danger to the present or to future generations
either as mutagens, carcinogens or teratogens. One of the
man made genotoxic chemicals, endosulfan, is sprayed
onto crops and the spray travels long distances before it
lands on crops, soil and water. It is an insecticide with
estrogenic activity that is toxic to many fish and
mammals. Some reports suggested that it could
accumulate in aquatic animals and cause human fatalities.
Exposure to endosulfan happens mostly from eating
contaminated food, skin contact, breathing and drinking
contaminated water.
Since endosulfan is relatively labile and is
considerably less toxic to mammals compared with other
cyclodiene insecticides (Goebel et al., 1982;
Sutherland et al., 2002), it has been widely used as a
broad-spectrum insecticide for the control of numerous
Corresponding Author: R. Saraswathy, Division of Biomolecules and Genetics, School of Biosciences and Technology,
VIT University, Vellore-632014, TamilNadu, India. Tel: 9443328424/ 91 416 2202390/ 2202373;
Fax: 91-416-2243092 / 224041
17
Asian J. Med. Sci., 3(1): 17-22, 2011
Table 1: The frequency and the nature of clinical deformities observed
in endosulfan exposed individuals from Kasaragod area
No. of individuals
Family
studied in the
S.No. code
Diagnosis /No. of affecteds
family
1
ENS -1
Mental retardation, seizures and 5
cerebral palsy / 9 yr old male
affected
2
ENS -2
Mental retardation, deformities 4
of hands and legs / 24 yr old
male affected
3
ENS -3
Osteogenesis imperfecta, limb 6
deformities /9 yr and 12 yr
females (sisters) affected
4
ENS - 4 Mental retardation,
4
hepatospleenomegaly and
hydrocephaly/ 6 yr old male
affected
5
EN -1
Mental retardation, paralysis,
5
locomotor problem, speech
problem, strabismus / 6 yr
old male affected
6
EN -3
Uterine, bone marrow cancer/
3
45 yr old female affected
7
EN -4
Optical atrophy, nystagmus/
4
8 yr and 10 yr old males
(brothers) affected
8
EN -5
Muscular dystrophy/8 yr and
4
11 yr old males (brothers)
affected
11 affecteds
35 individuals /
8 families
years on cashew nut plantations situated on hilltops in
some villages of northern Kerala, India. The population
living in the valley had a significant chance of exposure
to this pesticide during aerial spray and subsequently
through other contaminated environmental media. This
population, therefore, provided a unique opportunity to
study the long-term health effects of endosulfan. Hence
for this study the subjects were selected from Kasaragod
district, a hilltop area in Kerala, India.
MATERIALS AND METHODS
Area of study: Endosulfan had been aerially sprayed two
to three times a year for more than 20 years on cashew nut
plantations situated on hilltops in some villages of
northern Kerala, India. As the population living in the
valley had a significant chance of exposure to this
pesticide during aerial spray and subsequently through
other contaminated environmental media, therefore, it
would provide a unique opportunity to study the longterm health effects of endosulfan, on human habitants of
this area.
Selection of study and control areas: The exposed
populations were permanent residents of the village
situated below the cashew plantations where endosulfan
had been sprayed aerially. These villages had 12 firstorder streams originating from the cashew plantations.
Most of the habitations were along the valleys and close
to the stream banks, and they depended on runoff water
for irrigation purposes. A total of 6 panchayats in the
district which had the incidence of severe cases were
selected for this study. Eight families consisting of 35
individuals were selected for clinical studies and 16
subjects were used for cytogenetic analysis.
Chromosomal aberration analysis: Chromosome
preparations
were
obtained
from
PHA
(phytohemagglutinin) stimulated peripheral blood
lymphocytes
by
using modified method of
Hungerford (1965). At least fifty well spread metaphase
plates were scored by direct microscopic analysis. Well
spread metaphases were photographed under oil
immersion objective lens (100X) Leica DM2000
microscope with metasystem camera & photomicrographs
of banded spreads were karyotyped using automatic
IKaros software (metasystems). The karyotype was
described according to International System for human
Cytogenetic Nomenclature (ISCN, 2005).
Study parameters: The study parameters included
recording of clinical history with the help of the
physicians in a specially designed proforma and pedigree
analysis of the families and cytogenetic studies using
chromosomal aberrations as endpoint.
RESULTS
Ethical aspects: The participants were told the objectives
of the study, and a consent form in local language was
read aloud to them and only in willing cases from whom
blood samples were collected.
The clinical nature of the study subjects’ and the
frequency of chromosomal aberrations analysed in
endosulfan exposed subjects are presented in Table 1 and
2, respectively.
Clinical examinations of all the 35 subjects belonging
to 8 families were recorded with the help of the
physicians. Eleven of them (31.4%) showed severe
clinical deformity ranging from mental retardation to bone
marrow cancer showing neurotoxicity and immunotoxic
effects of endosulfan exposure. They are given below.
Cytogenetic studies:
Collection, storage and transport of blood samples:
Five milliliters of venous blood were collected from each
willing individual and were transported to Biomedical
Genetics Research Lab at VIT University within 24 h for
culturing. To avoid observer bias, the samples were coded
before being handed over for analysis.
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Asian J. Med. Sci., 3(1): 17-22, 2011
13.3% chromosomal aberrations and father 35 years old
showed 44% chromosomal aberrations.
Family 1: Members studied were 5:
ENS-1-1: This family was reported to be living in
Panathady village since 14 years.
Family 5: Members studied were 5:
EN-1-1: This family was reported to be living in
Kamhangod village for more than 30 years.
Proband: The 9 year old boy showed delayed milestone
since 3 months of age. He had large head (circumference44.5 cm), flaccid extremities, seizures and cerebral palsy.
His chromosome complement showed 46, XY karyotype
and 13.3% chromosomal aberrations were observed.
Proband: The 6 year old boy showed mental retardation,
paralysis (right side), speech problem, strabismus and
locomotory problem. His chromosome complement
showed 46, XY karyotype and no chromosomal
aberrations were observed.
Parents of the proband: His parents were reported to be
clinically normal and were not available for sample
collection.
Parents of the proband: His parents were reported to be
clinically normal and his mother 29 years old showed
6.66% chromosomal aberrations. Father was not
available.
Grandparents of the proband: His grandparents
(maternal) were reported to be clinically normal. The
grandmother showed 10% chromosomal aberrations and
there were no chromosomal aberrations observed in
grandfather.
Grandparents of the proband: His grandmother
(paternal) was reported to be clinically normal. The
grandmother 65 years old showed no chromosomal
aberrations and grandfather died due to myocardial
infarction.
Relative of the proband: The maternal uncle aged 27
years was clinically normal; however 20% chromosomal
aberrations were observed in him.
Family 2: Members studied were 4:
ENS-2-3: This family was reported to be living in
Cheravathoor village, Kasaragod since 27 years.
Relative of the proband: His brother aged 8 years was
clinically normal; no chromosomal aberrations were
observed.
Proband: The 24 year old male showed mental
retardation, deformities of hands and legs.
Family 6: Member studied was 3:
EN-3-2: 52 years old male living in Rajapuram panchayat
for more than 40 years was reported to be clinically
normal. His chromosome karyotype was 46, XY and 10%
chromosomal aberrations were observed.
Parents of the proband: His parents were reported to be
clinically normal. Proband’s mother 43 years old showed
10% chromosomal aberrations and father 48 years old
showed 6.66% chromosomal aberrations.
Family 7: Members studied were 4:
EN-4-3: 34 years old male living in Enmakaje panchayath
for more than 30 years was reported to be clinically
normal. His chromosome karyotype was 46, XY and 15%
chromosomal aberrations were observed. He worked in
the field. His children (2 boys) have optical atrophy and
nystagmus.
Family 3: Members studied were 6:
ENS-3-6: 77 years old female living in Kumbadaje
village, Kasaragod for more than 40 years was reported to
be clinically normal. Her chromosome karyotype was 46,
XX and 5% chromosomal aberrations were observed. She
worked in the field. Her two grand daughters were born
with limb deformities and osteogenesis imperfecta.
Family 8: Members studied were 4:
EN-5-3: This family lived in Bellur panchayath for more
than 14 years and the parents are reported to be clinically
normal. Two sons aged 8 years and 11 years were affected
with muscular dystrophy.
The cytogenetic studies were carried out using
peripheral blood leucocyte cultures and giemsa banding
technology and scoring chromosome aberrations as
endpoint. It was observed that a chromosome aberration
per cell was 0.121±0.09 which was significantly higher,
when compared with the control samples showing
0.014±0.0001 aberrations per cell (Table 2).
Family 4: Members studied were 4:
ENS-4-1: This family was reported to be living in
Kanjambady village, Kasaragod since 6 years.
Proband: The 6 year old boy showed mental retardation,
hydrocephaly and hepatospleenomegaly. His chromosome
complement showed 46, XY karyotype and 5%
chromosomal aberrations were observed.
Parents of the proband: His parents were reported to be
clinically normal. Proband’s mother 34 years old showed
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Asian J. Med. Sci., 3(1): 17-22, 2011
Table 2: Frequency of chromosomal aberrations analysed in endosulfan
exposed patients
No. of
No. of
metaphases chromosomal Aberration
S No. Patients
sex/age analysed
aberrations
per cell
1.
ENS 1-1
M/9
50
7
0.14
2.
ENS 1-3
M/56
50
2
0.04
3.
ENS 1-4
M/27
50
10
0.2
4.
ENS 1-5
F/48
50
5
0.1
5.
ENS 2-3
M/48
50
4
0.08
6.
ENS 2-4
F/43
50
7
0.14
7.
ENS 3-6
F/77
50
4
0.08
8.
ENS 4-1
M/6
50
4
0.08
9.
ENS 4-2
F/34
50
7
0.14
10
ENS 4-3
M/35
50
22
0.44
11.
EN 1-1
M/6
50
3
0.06
12.
EN 1-2
F/29
50
4
0.08
13.
EN 1-3
M/8
50
4
0.08
14.
EN 1-4
F/65
50
4
0.08
15.
EN 3-2
M/52
50
5
0.1
16.
EN 4-3
M/34
50
5
0.1
800
97
0.121
Endosulfan exposed patients: Aberration per cell = 97/800 = 0.121;
S.D. = ±0.09, Control: Aberration per cell = 7/500 = 0.014; Mean±SD
= 0.014±0.0001
Human poisonings: The worst of all the cases so far
reported are from three nations; Cuba, Benin and India. In
Cuba- Endosulfan was responsible for the death of 15
people in the western province of Matanzas, Cuba in
February 1999. A total of 63 people became ill after
consuming food contaminated with endosulfan according
to Cuban authorities (Anonymous, 1999). In Borgou
province in Benin, endosulfan poisoning caused many
deaths during 1999-2000 cotton season. Official records
state that at least 37 deaths occurred and 36 were taken
seriously ill. In the same region in1999 a boy died
after eating corn contaminated with endosulfan
(Ton et al., 2000). In South India- People in 15 villages in
Kasaragod in the South Indian State of Kerala were
subjected to continuous exposure to endosulfan which
was aerially sprayed three times every year for 24 years.
Congenital Birth defects reproductive health problems,
Cancers, loss of immunity, neurological and mental
diseases were reported among the villagers. Following a
public outcry a number of health based scientific studies
confirmed that the health problems were directly linked to
the exposure to endosulfan (Thanal Conservation Action
and Information Network, Thiruvananthapuram, Kerala,
India, 2001; Anonymous, 2002; Quijano, 2002).
In this study also the hazardous nature of endosulfan
exposure on the human population is confirmed. Out of 35
subjects studied 11 of them (31.4%) had severe clinical
deformity (Table 1).
For the clinical and pedigree analysis we examined
the thoroughly every one of 35 subjects with the help of
qualified physicians. Out of the 11 physically deformed
subjects, 4 of them had mental retardation showing a
neurotoxic effect of endosulfan. Neurotoxicity and
endocrine-disruption potential of endosulfan was also
demonstrated in animal experiments (Hiremath and
Kaliwal, 2002) in vitro assays (Kang et al., 2001; Bisson
and Hontela, 2002). Endosulfan activity was observed in
human Jurkat T-cell (Kannan et al., 2000; Kannan and
Jain, 2003). And hence this pesticide has been banned or
restricted its use. A ban on endosulfan exists in the South
Indian state of Kerala (imposed through a Court Order),
which came as a result of a public pressure following the
poisoning of many villages due to aerial spraying of the
chemical.
Endosulfan has also been detected from human
tissues. It has been detected from cord blood samples
obtained at the time of delivery and in human sera.
Alarmingly high levels of endosulfan residues were
observed in human blood and breast milk in a study in
Kasaragod in Kerala, India.
However, several independent studies have shown
that endosulfan is genotoxic, using aquatic animals for
evaluation (Lajmanovich et al., 2005). Data from in vitro
and in vivo mutagenicity studies generally provide
DISCUSSION
Endosulfan is a pesticide belonging to the
organochlorine group of pesticides, under the Cyclodiene
subgroup. It emerged as a leading chemical used against
a broad spectrum of insects and mites in agriculture and
allied sectors. It acts as contact and stomach poison and
has a slight fumigant action It is used in vegetables fruits,
paddy, cotton, cashew, tea, coffee, tobacco and timber
crops It is also used as a wood preservative and to control
tsetse flies and termites It is not recommended for
household use. Intentional misuse of endosulfan for
killing fish and snails has also been reported. Endosulfan
was also reported as used deliberately as a method of
removing unwanted fish from lakes before restoring.
Endosulfan was introduced at a time when
environmental awareness and knowledge about the
environmental fate and toxicology of such chemicals were
low and not mandatory as per national laws. But now it is
being detected as an important cause of pesticide
poisoning in many countries.
Endosulfan has been in world-wide use since its
introduction in the 1950’s. It was considered a safer
alternative to other organochlorine pesticides in many
countries in all regions since the 1970’s. But in the last
two decades many countries have recognized the hazards
of wide application of endosulfan.
For instance, cases of endosulfan poisoning have
been reported from many parts of the world Accidental
and intentional exposure leading to human fatalities and
environmental tragedies has occurred. The following are
some of the major cases of poisoning.
20
Asian J. Med. Sci., 3(1): 17-22, 2011
evidence that endosulfan is mutagenic, clastogenic,
induces effects on cell cycle kinetics and DNA strand
breaks (Yadav et al., 1982; Lu et al., 2000; Jamil
et al., 2004). Endosulfan was also found to cause
chromosomal aberrations in hamster and mouse, sexlinked recessive mutations in Drosophila, and dominant
lethal mutations in mice (Velázquez et al., 1984; Naqvi
and Vaisnavi 1993; Jamil et al., 2004). It is also known to
cause mutations in mammals (Pandey et al., 1990). It may
induce mutations in human, if exposure is great. It is also
a potential tumor promoter (Fransson-Steen et al., 1992).
The genotoxic effect of endosulfan on erythrocytes of
amphibian tadpoles was reported (Lajmanovich et al.,
2005). It is important to note that the occurrence of
nuclear morphological aberrations in H. puchella, as well
as the general degenerative changes in erythrocytes during
the tadpole stages studied, corresponded to a period of
intense hematopoiesis with active cell division in the
circulating blood (Lajmanovich et al., 2005).
The immunotoxic and genotoxic effect of endosulfan,
an organochlorine insecticide, on sheep peripheral blood
leukocytes was examined in vitro conditions. Our studies
also provide evidence both for genotoxic and
immunotoxic effects of endosulfan. The immunotoxic
effect was evaluated by assays of the metabolic activity of
phagocytes and assays for lymphocyte activation-the
Leucocyte Migration-Inhibition Assay (LMIA) and
lympho-proliferation. The significant inhibitory effect of
endosulfan on metabolic activity of peripheral blood
phagocytes was registered at the actual concentrations of
10(-3), 10(-4)M. At 10(-3)M the migration of leukocytes
was inhibited, both in activated and non-activated with
phytohemagglutinin (PHA) leukocyte suspensions
(p<0.01) in LMIA.
This indicated the direct cytotoxic effect of
endosulfan on the polymorphonuclears and monocytes of
which the intensity of migration is an indicator of
lymphocyte activation with mitogen. At the concentration
of 10(-4) M an immunotoxic effect, ie. Significant
decrease of lymphocyte activation with mitogen was
recorded in LMIA. Lymphoproliferation test showed the
significant inhibition of proliferation for PHA-stimulated
lymphocytes at 10(-3) M and 10(-4) M. Micronucleus
assay evaluated the genotoxic potential of endosulfan.
Higher concentrations of insecticide 10(-5)M, 10(-6)M
resulted in a significant dose dependent increase in the
number of micronuclei (Pistl et al., 2003).
In this study the genotoxic effects of endosulfan was
evaluated by using chromosomal aberrations as the end
point in the leucocyte cultures of the subjects exposed to
endosulfan for several years. It was observed that the
chromosomal aberrations per cell in an endosulfan
exposed subject is 0.121±0.09 which was significantly
much higher than that of the control (0.014±0.0001).
CONCLUSION
There exists contradicting results of the
environmental samples of endosulfan residues present in
the soil and water samples obtained after endosulfan spray
that may cause genotoxic effects in human health. Centre
for Science and Environment (CSE) New Delhi analysed
biological and environmental samples for Endosulfan
residues on 2001, about one and a half month after the last
aerial spray of Endosulfan carried out. The results
published in the magazine “Down to Earth” showed that
the concentration of Endosulfan in three water samples
were 7 to 51 times higher than the Maximum Residue
Limit (MRL). Very high levels of Endosulfan were
reported in samples of human blood, human breast milk,
vegetables, spices, cow’s milk, animal tissues, cashew,
cashew leaves and soil. In one of the soil sample the
levels of Endosulfan were 391 times higher than MRL.
Fredrick Institute of Plant Protection and Toxicology
(FIPPAT) at the request of PCK carried out evaluation of
Endosulfan residues in 106 samples of human blood, one
cow milk sample, one fish sample, 30 water samples, 29
soil samples and 28 cashew leaf samples collected from
18.3.2001 to 02.05.2001 from Padre village. Their results
show that there are no residues of Endosulfan in any of
the blood samples, cow milk and water samples.
However, some residue of Endosulfan was detected in soil
and leaf samples. This study provide evidence for a
significant increase in the chromosomal aberration in the
human exposed to endosulfan, yet, there is no direct
evidence to attribute to these effects to endosulfan
pollution, but there is no evidence to completely deny it
also. Hence it requires in vivo studies to confirm it. Hence
it is planned to do in vivo studies using endosulfan on
human leucocyte cultures.
ACKNOWLEDGEMENT
The authors would like to thank VIT authorities for
providing facilities to carry out this study.
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